WO2003/066635 describes a number of diazabicycle derivatives as antagonists of tachykinin receptors, also known as substance P (SP) receptors or NK receptors and in particular NK-1 receptors, including the 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro-pyrrolo[1,2-α]-pyrazin-2-yl)-piperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (otherwise known as orvepitant).
Orvepitant, otherwise known as 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro-pyrrolo[1,2-α]-pyrazin-2-yl)-piperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide has the following chemical structure (I).

Hereinafter any reference to orvepitant refers to the compound (I).
Orvepitant may also be known as:
CAS Index name
1-Piperidinecarboxamide, N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-4-[(8aS)-hexahydro-6-oxopyrrolo[1,2-α]pyrazin-2(1H)-yl]-N-methyl-, (2R,4S)
and
IUPAC name:
(2R,4S)—N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-[(8aS)-6-oxohexahydropyrrolo[1,2-α]pyrazin-2(1H)-yl]-1-piperidinecarboxamide.
A preferred salt of the compound (I) is its hydrochloride salt which is otherwise known as orvepitant hydrochloride.
A further preferred salt of the compound (I) is its maleate salt which is otherwise known as orvepitant maleate.
WO2009/124996 describes a new crystalline form of orvepitant maleate namely anhydrous crystalline form (Form1).
The compound (I), pharmaceutically acceptable salts thereof are described in the aforementioned specifications as antagonists of tachykinin receptors, also known as substance P (SP) receptors or NK receptors and in particular NK-1 receptors, both in vitro and in vivo and are thus of use in the treatment of conditions mediated by tachykinins, including SP and other neurokinins.
Particularly, the compound (I), and pharmaceutically acceptable salts or solvates thereof are described as useful in the treatment of central nervous system (CNS) disorders.
We have now surprisingly found that the compound (I) or pharmaceutically acceptable salts thereof are also useful in the treatment of chronic cough.
Particularly, we have found that the compound (I) or pharmaceutically acceptable salts thereof are useful in the treatment of refractory chronic cough.
Refractory chronic cough also known as chronic refractory cough, chronic unexplained cough, chronic undiagnosed cough, chronic idiopathic cough, cough hypersensitivity syndrome, chronic intractable cough or chronic treatment-resistant cough is defined as a chronic cough of 8-weeks for which either no objective evidence of an underlying cause can be determined after routine clinical investigation or a cough that did not respond to standard treatment for the identified underlying cause.
Cough is a defensive reflex action of the respiratory system that is activated to clear the upper airways (Chung & Pavord, Lancet 2008; 371:1364-74). However, excessive coughing is the commonest reason for patients seeking medical care (Burt & Schappert, Vital and health statistics. Series 13, Data from the National Health Survey 2004; (157):1-70; Schappert & Burt, Series 13, Data from the National Health Survey 2006; (159):1-66) and has a significant impact on patient quality of life (French et al., Archives of internal medicine 1998; 158(15):1657-61; French et al., Chest 2005; 127(6):1991-8).
Coughing is most commonly associated with viral upper respiratory tract infections, where this symptom usually resolves spontaneously within a 3 week period. Chronic coughing (in which persists in a troublesome form for more than eight weeks duration) however may affect up to 12% of the UK population (Ford et al., Thorax 2006; 61(11):975-9) and 18% of the US (Barbee et al., Chest. 1991; 99(1):20-6), afflicts women more often than men and generally has an onset from middle age (Ford et al., Thorax 2006; 61(11):975-9; Irwin et al., The American review of respiratory disease 1981; 123(4 Pt 1):413-7; Irwin et al., Chest 2006; 129(1 Suppl):1S-23S; Janson et al., The European respiratory journal: official journal of the European Society for Clinical Respiratory Physiology 2001; 18(4):647-54).
Chronic coughing may be associated with many conditions including interstitial lung diseases (also called parenchymal diseases) such as: emphysema, idiopathic pulmonary fibrosis (IPF) and sarcoidosis; airway diseases such as asthma, chronic bronchitis, chronic postnasal drip, eosinophilic bronchitis and chronic obstructive pulmonary disease; chronic infections such as: bronchiectasis, tuberculosis, cystic fibrosis; lung tumours such as: bronchogenic carcinoma, alveolar cell carcinoma, benign airway tumours, mediastinal tumours; cardiovascular disease such as: left ventricular failure, pulmonary infarction, aortic aneurysm; other diseases such as: reflux oesophagitis, recurrent aspiration, endobronchial sutures, postnasal drip syndrome or rhinosinusitis; drug related such as: administration of angiotensin-converting enzyme inhibitors (Chung & Pavord, Lancet 2008; 371:1364-74).
Chronic coughing has been shown to have significant physical, social and psychological consequences (Birring et al., Thorax 2003; 58(4):339-43; French et al., Chest 2002; 121(4):1123-31). Patients often suffer complications such as chest and abdominal pains, retching and vomiting, urinary incontinence and even cough syncope. Many are embarrassed and stigmatised by this symptom and therefore avoid public places and social gatherings. Depression scores in this patient population have been found to be comparable to those seen in other serious chronic illnesses such as rheumatoid arthritis and sickle cell disease (Dicpinigaitis et al., Chest 2006; 130(6):1839-43).
Clinicians cannot identify a treatable cause for chronic cough in about 40% of patients (Hague et al., Chest 2005; 127(5):1710-3); as a result the treatment options for these chronic treatment-refractory cough patients are very limited (Gibson & Vertigan, BMJ. 2015; 351:h5590). To date the only drug therapies that have been shown to be effective in randomised controlled trials in this patient group are morphine (Morice et al., American journal of respiratory and critical care medicine 2007; 175(4):312-5) and gabapentin (Ryan et al., Lancet. 2012; 380(9853):1583-9). Other studies have suggested treatments such as amitriptyline and pregabalin (Halum et al., The Laryngoscope 2009; 119(9):1844-7) may be of help, but all these available pharmacological treatment choices are frequently associated with intolerable side effects such as drowsiness, tiredness, gastrointestinal disturbances, and some of these agents, such as for example morphine, are also addictive.
Thus there is an urgent need to identify new, effective and well-tolerated therapies for this debilitating condition to alleviate patient suffering.